ASSESSING THE CLINICAL IMPACTS OF IMMUNOMODULATORY WITHDRAWAL FROM ANTI-TNF COMBINATION THERAPY IN PEDIATRIC INFLAMMTORY BOWEL DISEASE

Abstract

Abstract INTRODUCTION Combination therapy consists of both a monoclonal antibody against tumor necrosis factor (anti-TNF) (infliximab (IFX) or adalimumab (ADA)) and an immunomodulator (IMM) (thiopurines (TP) or methotrexate (MTX)). Although combination therapy improves clinical outcomes, the IMM may be discontinued to mitigate the risk of IMM-related adverse events. However, it is unknown how de-escalation impacts clinical outcomes in children with IBD. METHODS This is a retrospective review of pediatric patients with IBD (<18 years of age) initiated on combination therapy between January 2014 and December 2019. Demographic and laboratory data were recorded at initiation of combination therapy, prior to IMM discontinuation, and between 6-12 months after de-escalation. The primary objectives were to assess the impacts of de-escalation on clinical remission rates, laboratory markers, and anti-TNF trough levels, and to evaluate factors that predict a poor response to de-escalation. Linear mixed effects models with random intercepts accounting for correlated measures with a patient across time were used to compare differences between study groups (and subgroups). Chi-square and Kruskal-Wallis tests were used for comparisons between patients who did and did not require subsequent escalation. Hypothesis testing was conducted at an alpha of 0.05. RESULTS We included 152 pediatric patients, of whom 126 patients had CD and 26 patients had UC/IC. The mean age of initiating combination therapy was 13.76 (± 3.1) years, and the mean duration of combination therapy was 106 (± 56) weeks. De-escalation did not increase the risk of worsening disease activity or affect laboratory values, including albumin, hemoglobin, sedimentation rate, and c-reactive protein. In patients with CD on IFX and TP, calprotectin significantly increased from 107 ug/g to 383 ug/g (p<0.05) and anti-TNF trough levels significantly decreased from 19 ug/ml to 14 ug/ml (p<0.05) after de-escalation. Eighteen percent (27 patients) of patients required subsequent escalation in therapy. Amongst these patients, anti-TNF levels were lower and CRP and ESR were higher prior to de-escalation compared to patients who did not require adjustments (p<0.05). DISCUSSION Only patients with CD on IFX who discontinued the TP had a significant increase in fecal calprotectin and decrease in IFX levels, though the drug levels remained within therapeutic range >10 ug/ml, and there was no increased risk of worsening disease. Lower anti-TNF levels and higher inflammatory markers prior to de-escalation may be predictive of patients requiring escalation in therapy after stopping the IMM. De-escalation in children on combination therapy may be safely considered with close attention to clinical symptoms, inflammatory markers, and anti-TNF drug levels, especially in children with CD on IFX and TP combination therapy.